The present invention relates to a method of control of parasites in animals, compositions comprising a compound effective for the said control and compounds effective against parasites.
It is generally a goal of agronomists and veterinarians to possess sufficient means to control pests, particularly arthropods, when they attempt to invade or attack mammals, particularly domestic animals and/or livestock. A classical method of controlling such pests has been the use of topical and/or systemic pesticides on or in the domestic animal which is being attacked. Generally effective treatments include the oral administration of insect growth regulators, such as lufenuron, or antihelminth compounds such as an ivermectin or an avermectin, or the topical application of the insecticide fipronil. It is advantageous to apply pesticides to animals in oral form so as to prevent the possible contamination of humans or the surrounding environment. It is an object of the present invention to provide new pesticides which may be used in domestic animals.
Another object of the invention is to provide safer pesticides for domestic animals.
Another object of the invention is to provide new pesticides for domestic animals that may be used in lower doses than existing pesticides.
These objects are met in whole or in part by the present invention.
U.S. Pat. No. 5,079,370, EP-A 0,846,686, WO 98/24769 and WO 97/28126 disclose the use of arylpyrazoles as parasiticidal agents. However, these references are completely silent on the problem that anti parasitical agents often elicit emesis in the animal to be protected or cured from the parasites.
The present invention provides a method of controlling parasites in or on an animal comprising administering, preferably orally, to the animal a parasiticidally effective, substantially non-emetic amount of a 1-arylpyrazole of formula (I): 
wherein:
R201 is cyano, C(O)alkyl, C(S)NH2, C(NH)OR203, C(NH)SR203, alkyl, C(xe2x95x90NOH)NH2, C(xe2x95x90NNH2)NH2, C(O)NH2, C(O)NHR205, C(O)NR205R206, haloalkyl or heterocyclyl from the group: 
optionally substituted by R203;
R202 is S(O)hR203, C2-C6 alkenyl, C2-C6 haloalkenyl, cycloalkyl, halocycloalkyl, cycloalkyl-alkyl , C2-C6 alkynyl, nitro or imidazol-2-yl optionally substituted by alkyl, alkoxy, haloalkyl, halogen, cyano and/or nitro;
R203 is alkyl or haloalkyl;
R204 is xe2x80x94OH, R205Oxe2x80x94, HC(O)Oxe2x80x94, R205C(O)Oxe2x80x94, R205OC(O)Oxe2x80x94, NH2C(O)Oxe2x80x94, R205NHC(O)Oxe2x80x94, R205R206NC(O)Oxe2x80x94, R205S(O)nC(O)Oxe2x80x94, R206SO2Oxe2x80x94, aryl-SO2Oxe2x80x94, (C4-C7)-oxacycloalkyloxy, R205R206Nxe2x80x94C(NR205)xe2x80x94Oxe2x80x94, R205R206Nxe2x80x94C(NH)xe2x80x94Oxe2x80x94, R205NHxe2x80x94C(NR205)xe2x80x94Oxe2x80x94, R205NHxe2x80x94C(NH)xe2x80x94Oxe2x80x94, R205Nxe2x95x90CHxe2x80x94Oxe2x80x94, R205Nxe2x95x90C(R206)xe2x80x94Oxe2x80x94, R205NHxe2x80x94C(S)xe2x80x94Oxe2x80x94, R205R206Nxe2x80x94C(S)xe2x80x94Oxe2x80x94;
R205 is alkyl, haloalkyl, cycloalkyl, halocycloalkyl, alkoxyalkyl, haloalkoxyalkyl, adamantyl, aminoalkyl, alkylaminoalkyl, dialkylaminoalkyl, haloalkylaminoalkyl, di(haloalkyl)aminoalkyl, aryl optionally substituted, hetaryl optionally substituted, arylalkyl optionally substituted, hetarylalkyl optionally substituted, C2-C6 alkenyl, C2-C6 alkinyl;
R206 is alkyl, haloalkyl, cycloalkyl, halocycloalkyl, alkoxyalkyl, haloalkoxyalkyl, aryl optionally substituted, hetaryl optionally substituted, arylalkyl optionally substituted, hetarylalkyl optionally substituted;
or R205 and R206 may form together with the nitrogen to which they are attached a 3 to 7 membered ring which additionally may contain one or more heteroatoms selected from nitrogen, oxygen and sulfur;
X1 is selected from nitrogen and Cxe2x80x94R212;
R211, R212 are independently selected from halogen, hydrogen, CN, C1-C3 alkyl and NO2;
R213 is selected from halogen, haloalkyl, haloalkoxy, xe2x80x94S(O)kCF3, and xe2x80x94SF5 or forms a ring with R214;
R214 is hydrogen or may constitute together with R213 a group of OCF2O, CF2OCF2, CF2OCF2O and CF2CF2O, which forms together with the carbons they are attached to a five to six membered ring; and
h, k and n are independently selected from 0, 1, and 2;
and veterinarily acceptable salts thereof.
By the term xe2x80x9cveterinariiy acceptable saltsxe2x80x9d is meant salts the anions of which are known and accepted in the art for the formation of salts for veterinary use. Suitable acid addition salts, e.g. formed by compounds of formula (I) containing a basic nitrogen atom, e.g. an amino group, include salts with inorganic acids, for example hydrochlorides, sulphates, phosphates and nitrates and salts with organic acids for example acetic acid.
When R204 is OH the pyrazole structure can also be exhibited by its tautomeric form as pyrazolon structure.
Unless otherwise specified, alkyl and alkoxy groups are straight chain or branched and are generally lower alkyl and alkoxy groups, that is having from one to six carbon atoms, preferably from one to four carbon atoms. Generally, the haloalkyl, haloalkoxy and haloalkylamino groups have from one to four carbon atoms. Halogen means F, Cl, Br, and I, preferably F and Cl. The haloalkyl and haloalkoxy and haloalkylamino groups can bear one or more halogen atoms; preferred groups of this type include xe2x80x94CF3 and xe2x80x94OCF3. Cycloalkyl groups generally have from 3 to 6 carbon atoms, preferably from 3 to 5 carbon atoms and may be substituted by one or more halogen atoms. Preferably in compounds of formula (I), alkyl groups are generally substituted by from one to five halogen atoms, preferably from one to three halogen atoms. Chlorine and fluorine atoms are preferred.
In compounds of formula (I) the following examples of radicals are provided:
An example of cycloalkylalkyl is cyclopropylmethyl;
an example of cycloalkoxy is cyclopropyloxy; and
an example of alkoxyalkyl is CH3OCH2xe2x80x94.
Generally, in dialkylamino or di(haloalkyl)amino radicals, the alkyl and haloalkyl groups on nitrogen may be chosen independently of one another.
Generally, the term xe2x80x9carylxe2x80x9d means a carbocyclic aromatic radical having preferably 6 to 14, in particular 6 to 12, carbon atoms, for example phenyl, naphthyl or biphenylyl, preferably phenyl;
the term xe2x80x9cheterocyclylxe2x80x9d preferably a hetaryl or heteroaliphatic ring system, xe2x80x9chetarylxe2x80x9d preferably being understood as meaning an aryl radical in which at least one CH group is replaced by N and/or at least two adjacent CH groups are replaced by S, NH or O, for example a radical of thiophene, furan, pyrrole, thiazole, oxazole, imidazole, isothiazole, isoxazole, pyrazole, 1,3,4-oxadiazole, 1,3,4-thiadiazole, 1,3,4-triazole, 1,2,4-oxadiazole, 1,2,4-thiadiazole, 1,2,4-triazole, 1,2,3-triazole, 1,2,3,4-tetrazole, benzo[b]thiophene, benzo[b]furan, indole, benzo[c]thiophene, benzo[c]furan, isoindole, benzoxazole, benzothiazole, benzimidazole, benzisoxazole, benzisothiazole, benzopyrazole, benzothiadiazole, benzotriazole, dibenzofuran, dibenzothiophene, carbazole, pyridine, pyrazine, pyrimidine, pyridazine, 1,3,5-triazine, 1,2,4triazine, 1,2,4,5-triazine, quinoline, isoquinoline, quinoxaline, quinazoline, cinnoline, 1,8-naphthyridine, 1,5-naphthyridine, 1,6-naphthyridine, 1,7-naphthyridine, phthalazine, pyridopyrimidine, purine, pteridine or 4H-quinolizine;
and the term xe2x80x9cheteroaliphatic ring systemxe2x80x9d preferably a (C3-C8)cycloalkyl radical in which at least one carbon unit is replaced by O, S or a group NRxe2x80x2 and Rxe2x80x2 is hydrogen, (C1-C4)alkyl, (C1-C4)alkanoyl, (C1-C4)alkoxycarbonyl, (C1-C4)alkylsulfonyl, (C1-C4)alkoxy or aryl;
The substituents with which the various aliphatic, cycloaliphatic, aromatic and heterocyclic ring systems can be provided are, for example, halogen, nitro, cyano, di-(C1-C4)alkylamino, (C1-C4)alkyl, (C1-C8)cycloalkyl, (C1-C4)trialkylsilyl, (C1-C4)alkoxy, (C1-C4)alkoxy-(C1-C4)alkyl, (C1-C2)alkoxy-[CH2CH2O]0,1,2-ethoxy, (C1-C4)alkylthio, (C1-C4)alkylsulfinyl, (C1-C4)alkylsulfonyl, phenyl, benzyl, phenoxy, halophenoxy, (C1-C4)alkylphenoxy, (C1-C4)alkoxyphenoxy, phenylthio, heterocyclyl, heterocyclylthio or heterocyclyloxy, it being possible for one or more, in the case of fluorine also up to the maximum number of, hydrogen atoms in the alkyl radicals and the radicals derived therefrom to be replaced by halogen, preferably chlorine or fluorine, where, in the event that these substituents are (C1-C4)alkyl, they may also be linked cyclically and where one or two aliphatic carbon units in these fused ring systems, such as, for example, the indane, di-, tetra- or decahydronaphthyl or benzocycloheptane system, may be replaced by heteroatom units such as oxygen or sulfur and where one or more, in the case of fluorine also up to the maximum number of, hydrogen atoms on the aliphatic carbon atom units can be replaced by halogen or (C1-C4)alkyl.
It is also to be understood that enantiomeric and diastereomeric forms of the compounds of formulae (I) and salts thereof are embraced by the present invention.
By the term non-emetic is meant a compound that does not generally elicit emesis from the animal when a protective, preventative or cleaning dose is administered to the animal. By the term emesis is meant vomiting. Generally an emetic substance elicits the said emesis in less than 24 hours after administration, preferably less than 8 hours, more preferably less than 2 hours. Generally when the compounds of the invention are administered to a population of animals, more than 70% of the animals are free of emesis, preferably more than 80%, most preferably more than 90%.
Preferred compounds of the formula (I) are those wherein:
R201 is cyano, C(O)alkyl, C(S)NH2, alkyl, C(xe2x95x90NOH)NH2 or C(xe2x95x90NNH2)NH2;
R202 is S(O)hR203, C2-C3 alkenyl, C2-C3 haloalkenyl, cycloalkyl, halocycloalkyl, cycloalkyl-alkyl , C2-C3 alkynyl;
R203 is alkyl or haloalkyl;
R204 is xe2x80x94OH, R205Oxe2x80x94, HC(O)Oxe2x80x94, R205C(O)Oxe2x80x94, R205OC(O)Oxe2x80x94, NH2C(O)Oxe2x80x94, R205NHC(O)Oxe2x80x94,
R205R206NC(O)Oxe2x80x94, R205S(O)nC(O)Oxe2x80x94;
R205 is alkyl, haloalkyl, cycloalkyl, halocycloalkyl, alkoxyalkyl, haloalkoxyalkyl, aminoalkyl, alkylaminoalkyl, dialkylaminoalkyl, haloalkylaminoalkyl, di(haloalkyl)aminoalkyl,
R206 is alkyl, haloalkyl, cycloalkyl, halocycloalkyl, alkoxyalkyl, haloalkoxyalkyl, or R205 and R206 may form together with the nitrogen to which they are attached a 3 to 7 membered ring which additionally may contain one or more heteroatoms selected from nitrogen, oxygen and sulfur;
X1 is selected from nitrogen and Cxe2x80x94R212;
R211, R212 are independently selected from halogen, hydrogen, CN, and NO2;
R213 is selected from halogen, haloalkyl, haloalkoxy, xe2x80x94S(O)kCF3, and xe2x80x94SF5 
R214 is hydrogen; and
h, k and n are independently selected from 0, 1, and 2.
Further compounds of formula (I) which are preferred according to the present intention are those wherein:
R201 is cyano;
R202 is S(O)hR203;
R203 is alkyl or haloalkyl;
R204 is OH or R205O;
X1 is selected from nitrogen and Cxe2x80x94R212;
R211 and R212 are independently selected from halogen, hydrogen, CN and NO2;
R213 is selected from halogen, haloalkyl, haloalkoxy, xe2x80x94S(O)kCF3, and xe2x80x94SF5; and
h and k are independently selected from 0, 1, and 2.
The compounds of formula (I) of the present invention preferably have one or more of the following features:
R201 is cyano;
R203 is halomethyl, preferably CF3;
R211, and R212are independently halogen;
X1 is Cxe2x80x94R212;
R213 is haloalkyl, haloalkoxy or xe2x80x94SF5; or
h is 0 or 1, or 2.
A further embodiment of the invention includes compounds of the formula (I), with the proviso that if R201 is CN and R202 is S(O)hR203 then R204 is not R205O or R205R206Nxe2x80x94C(O)xe2x80x94Oxe2x80x94.
In another aspect of the present invention there is provided a method of controlling parasites in or on an animal by administering to the animal an 1-arylpyrazole of formula (II): 
wherein:
R21 is cyano, C(xe2x95x90S)NH2, C(xe2x95x90NOH)NH2 or C(xe2x95x90NNH2)NH2;
R22 is S(O)mR23;
R23 is alkyl or haloalkyl;
R24 is OH, HC(O)Oxe2x80x94, R25C(O)Oxe2x80x94, R25OC(O)Oxe2x80x94, R26R25xe2x80x94Nxe2x80x94C(O)xe2x80x94Oxe2x80x94 or R25S(O)nC(O)Oxe2x80x94;
R25 is alkyl, haloalkyl, cycloalkyl, halocycloalkyl, alkoxyalkyl, haloalkoxyalkyl, adamantyl, adamantyl, aminoalkyl, alkylaminoalkyl, dialkylaminoalkyl, haloalkylaminoalkyl, di(haloalkyi)aminoalkyl, aryl optionally substituted, hetaryl optionally substituted, arylalkyl optionally substituted, hetarylalkyl optionally substituted, C2-C6 alkenyl, C2-C6 alkinyl;
or two groups R25 may form together with the nitrogen to which they are attached a 3 to 7 membered ring which additionally may contain one or more heteroatoms selected from nitrogen, oxygen and sulfur;
X is selected from nitrogen and Cxe2x80x94R32;
R31 and R32 are independently selected from halogen, hydrogen, CN, C1-C3 alkyl and NO2;
R33 is selected from halogen, haloalkyl, haloalkoxy, xe2x80x94S(O)rCF3, and xe2x80x94SF5 or forms a ring together with R34;
R34 is hydrogen or may constitute together with R213 a group of OCF2O, CF2OCF2, CF2OCF2O and CF2CF2O, which forms together with the carbons they are attached to a five to six membered ring;
m is 0, 1 or 2;
r is selected from 0, 1, and 2;
and veterinarily acceptable salts thereof;
provided that if R21 is cyano then R24 is not R25R25xe2x80x94Nxe2x80x94C(O)xe2x80x94Oxe2x80x94.
Preferred are compounds of formula (II),
wherein:
R21 is cyano, C(xe2x95x90S)NH2, C(xe2x95x90NOH)NH2 or C(xe2x95x90NNH2)NH2;
R22 is S(O)mR23;
R23 is alkyl or haloalkyl;
R24 is OH, HC(O)Oxe2x80x94, R25C(O)Oxe2x80x94, R25OC(O)Oxe2x80x94 or R25S(O)nC(O)Oxe2x80x94;
R25 is alkyl, haloalkyl, cycloalkyl, halocycloalkyl, alkoxyalkyl, haloalkoxyalkyl;
X is selected from nitrogen and Cxe2x80x94R32;
R31 and R32 are independently selected from halogen, hydrogen, CN, C1-C3 alkyl and NO2;
R33 is selected from halogen, haloalkyl, haloalkoxy, xe2x80x94S(O)rCF3, and xe2x80x94SF5 
In another aspect of the present invention there is provided a compound of formula (II) or salt thereof as hereinbefore described with the proviso that the compound is not 1-(2,6-dichloro-4-trifluoromethylphenyl)-3-cyano-4-trifluoromethylthio-5-hydroxypyrazole.
A further preferred class of compounds of formula (II) are those wherein:
R21 is cyano;
R22 is S(O)mR23;
R23 is haloalkyl, preferably CF3;
R24 is OH;
X is selected from nitrogen and Cxe2x80x94R32;
R31 and R32 are independently selected from halogen,
R33 is selected from halogen, haloalkyl, haloalkoxy, S(O)rCF3, and xe2x80x94SF5;
m and r are independently selected from 0, 1, and 2 with the proviso that the compound is not 1-(2,6-dichloro-4-trifluoromethylphenyl)-3-cyano-4-trifluoromethylthio-5-hydroxypyrazole.
In a further aspect of the invention the following groups of compounds are provided: Compounds of the formula (I), wherein
R201 is C(O)NH2, C(O)NHR205, C(O)NR205R206, C(O)Nxe2x95x90S(R203)2, haloalkyl or heterocyclyl from the group: 
optionally substituted by R203.
Compounds of the formula (I), wherein
R202 is nitro or imidazol-2-yl optionally substituted by alkyl, alkoxy, haloalkyl, halogen, cyano, nitro.
Compounds of the formula (I), wherein
R204 is R206SO2Oxe2x80x94, aryl-SO2Oxe2x80x94, (C4-C7)-oxacycloalkyloxy, R205R206Nxe2x80x94C(NR205)xe2x80x94Oxe2x80x94, R205R206Nxe2x80x94C(NH)xe2x80x94Oxe2x80x94, R205NHxe2x80x94C(NR205)xe2x80x94Oxe2x80x94, R205NHxe2x80x94C(NH)xe2x80x94Oxe2x80x94, R205Nxe2x95x90CHxe2x80x94Oxe2x80x94, R205Nxe2x95x90C(R206)xe2x80x94Oxe2x80x94, R205NHxe2x80x94C(S)xe2x80x94Oxe2x80x94, R205R206Nxe2x80x94C(S)xe2x80x94Oxe2x80x94.
Compounds of the formula (I), wherein
R214 constitute together with R213 a group of OCF2O, CF2OCF2, CF2OCF2O and CF2CF2O, which forms together with the carbons they are attached to a five to six membered ring.
The compounds 1-(2,6-dichloro-4-trifluoromethylphenyl)-3-cyano-4-trifluromethylsulfinyl-5-hydroxypyrazole and 1-(2,6-dichloro-4-trifluoromethylphenyl)-3-cyano-4-trifluromethylsulfonyl-5-hydroxypyrazole are highly preferred compounds according to the invention.
The following compounds of formula (I) are preferred according to the present invention as listed in Tables 1 to 3. The Compound Numbers are for identification purposes only. The following symbols are hereby defined: Me means methyl; Et means ethyl; n-Pr means n-propyl; i-Pr means isopropyl; n-Bu means n-Butyl; and Ph means Phenyl.
Methods of Synthesis
Method 1
The compounds of formula (I) and (II) with R204/R24xe2x95x90OH and R22xe2x95x90SR23 can be synthesized by reacting 5-hydroxypyrazoles with sulfenylchlorides with or without bases in organic solvents (see e.g. EP-A-295 117): 
Method 2
The compounds of formula (I) and (II) with R204/R24xe2x95x90OH and R22xe2x95x90SR23 can be synthesized by reacting 5-hydroxypyrazoles with disulfurdichloride. The resulting pyrazoledisulfides can be alkylated to yield 4-pyrazolsulfides (see e.g. EP-A-374 061, EP295117, C. Wakselman, J. Chem. Soc. Perkin Trans 1, 1992 3371-3375): 
Method 3
The compounds of formula (I) and (II) with R204/R24xe2x95x90OH and R22xe2x95x90S(O)aR23 (a=1,2) can be synthesized by reacting pyrazolsulfides R22xe2x95x90SR23 with oxidizing agents like peroxy compounds (hydrogenperoxide, organic peroxides as peroxyaceticacid), halogenderivatives (like periodate salts) and others to obtain sulfoxides R22xe2x95x90SOR23 and sulfones R22xe2x95x90SO2R23 (see e.g. EP-A-295 117). 
In another aspect of the present invention, compounds of formula (II) wherein R24 is HC(O)Oxe2x80x94, R25C(O)Oxe2x80x94, R25OC(O)Oxe2x80x94, or R25S(O)nC(O)O and R21, R22, R31, R33, X and n are defined above are generally prepared by reaction of compounds of formula (II) wherein R24 is OH and R21, R22, R31, R33, X and n are defined above with a compounds of formulae (III), (IV), (V), and (VI) respectively wherein X2 is a leaving group such as a halogen atom or an acetyl group:
Compounds of general formula (II) wherein of formula (II) wherein R24 is OH and R21, R22, R31, R33, X and n are defined above may be prepared by methods known in the art generally or by methods described in International Patent Publications WO 94/21606, WO 97/07102, WO 98/24767, WO 98/28277, WO 98/28278 and WO 98/28279, European Patent Application 385809, and U.S. Pat. Nos. 5,232,940, 5,047,550 or other methods known to the person skilled in the art.
The present invention also relates to a composition comprising a parasiticidally effective, substantially non-emetic amount of a compound of formula (I) or a salt thereof and an acceptable carrier. Acceptable carriers for the use of the compounds are generally known to the skilled addressee concerned with pest control in animals, particularly domestic animals, most preferably dogs or cats.
The compositions which can be used in the invention can comprise generally from about 0.001 to 95% of the compound of formula (I) or a salt thereof. The remainder of the composition up to 100% comprises a carrier as well as generally various additives. In this specification and the accompanying claims, percentages are by weight.
The diluted liquid formulations generally comprise from about 0.001 to about 3% of compound of formula (1) or a salt thereof, preferably from about 0.1 to about 0.5%. Solid formulations generally comprise from about 0.1 to about 8% of compound of formula (I) or a salt thereof, preferably from about 0.5 to about 1.5%.
Compositions for oral administration comprise one or more of the compounds of general formula (I) or salts thereof in association with veterinarily acceptable carriers or coatings and include, for example, tablets, pills, capsules, gels, drenches, medicated feeds, medicated drinking water, medicated dietary supplements, slow-release boluses or other slow-release devices intended to be retained within the gastro-intestinal tract. Any of these may incorporate the active ingredients contained within micro-capsules or coated with acid-labile or alkali-labile or other pharmaceutically acceptable enteric coatings. Feed premixes or concentrates containing compounds of the present invention for use in preparation of medicated diets, drinking water or other materials for consumption by animals may also be used. In a highly preferred embodiment, the compositions are administered postprandially, preferably from just after a meal to 2 hours after the meal. In a highly preferred embodiment, there is provided a product which is readily chewed by the animal and which product does generally not allow human contamination when the product is provided to the animal by hand.
The compounds of general formula (I) or salts thereof may be administered before, during or after meals. The compounds of general formula (i) or salts thereof may be mixed with a carrier and/or a foodstuff.
According to the present invention the compound of formula (I) or a salt thereof is administered orally in a dose to the animal in a dose range generally from 0.1 to 500 mg/kg of the compound of formula (I) or a salt thereof per kilogram of animal body weight (mg/kg), preferably from 1 to 100 mg/kg, more preferably from 1 to 50 mg/kg, even more preferably from 2 to 25 mg/kg, most preferably from 3 to 15 mg/kg According to the present invention, the frequency of treatment of the animal, preferably the domestic animal to be treated by the compound of formula (I) or a salt thereof is generally from about once per week to about once per year, preferably from about once every two weeks to about once every six months, more preferably from about once every two weeks to once every three months, and most preferably from about once every two weeks to about once every six weeks.
Generally the animal to be treated is a domestic animal, preferably a domestic companion animal. More preferably the animal to be treated is a dog and/or a cat.
Accordingly, in a preferred embodiment there is provided a method of controlling parasites in or on a cat comprising administering orally to the cat a parasitically effective, substantially non emetic amount of a 1-arylpyrazole of formula (I).
In a further preferred embodiment there is provided a method of controlling parasites in or on a dog comprising administering orally to the dog a parasitically effective, substantially non emetic amount of a 1-arylpyrazole of formula (I).
The present invention also relates to a composition comprising a parasiticidally effective amount of a compound of formula (II) or a salt thereof and an acceptable carrier. Acceptable carriers for the use of the compounds are generally known to the skilled addressee concerned with pest control in animals, particularly domestic animals, most preferably dogs or cats.
In another aspect of the present invention, the compounds of formula (II) or salts thereof may be used in the field of veterinary medicine or livestock husbandry or in the maintenance of public health against arthropods, helminths or protozoa which are parasitic internally or externally upon vertebrates, particularly warm-blooded vertebrates, for example domestic animals, e.g. cattle, sheep, goats, equines, swine, poultry, dogs or cats.
The compounds to animals infested by or exposed to infestation by arthropods, helminths or protozoa, by parenteral, oral or topical application of compositions in which the active ingredient exhibits an immediate and/or prolonged action over a period of time against the arthropods, helminths or protozoa, for example by incorporation in feed or suitable orally-ingestible pharmaceutical formulations, edible baits, salt licks, dietary supplements, pour-on formulations, sprays, baths, dips, showers, jets, dusts, greases, shampoos, creams, wax smears or livestock self-treatment systems.
Solid or liquid compositions for application topically to animals, timber, stored products or household goods usually contain from about 0.00005% to about 90%, more particularly from about 0.001% to about 10%, by weight of one or more compounds of formula (II) or veterinarily acceptable salts thereof. For administration to animals orally or parenterally, including percutaneously solid or liquid compositions, these normally contain from about 0.1% to about 90% by weight of one or more compounds of formula (II) or veterinarily acceptable salts thereof.
Medicated feedstuffs normally contain from about 0.001% to about 3% by weight of one or more compounds of formula (II) or veterinarily acceptable salts thereof.
Concentrates or supplements for mixing with feedstuffs normally contain from about 5% to about 90%, preferably from about 5% to about 50%, by weight of one or more compounds of formula (II) or veterinarily acceptable salts thereof. Mineral salt licks normally contain from about 0.1% to about 10% by weight of one or more compounds of formula (II) or veterinarily acceptable salts thereof.
Dusts or liquid compositions for application to livestock, goods, premises or outdoor areas may contain from about 0.0001% to about 15%, more especially from about 0.005% to about 2.0%, by weight, of one or more compounds of formula (II) or veterinarily acceptable salts thereof. Suitable concentrations in treated waters are between about 0.0001 ppm and about 20 ppm, more particularly about 0.001 ppm to about 5.0 ppm. of one or more compounds of formula (II), or veterinarily acceptable salts thereof, and may be used therapeutically in fish farming with appropriate exposure times. Edible baits may contain from about 0.01% to about 5%, preferably from about 0.01% to about 1.0%, by weight, of one or more compounds of formula (II) or veterinarily acceptable salts thereof.
When administered to vertebrates parenterally, orally or by percutaneous or other means, the dosage of compounds of formula (II), or veterinarily acceptable salts thereof, will depend upon the species, age, or health of the vertebrate and upon the nature and degree of its actual or potential infestation by arthropod, helminth or protozoan pests. A single dose of about 0.1 to about 500, preferably from 0.1 to about 100 mg, preferably about 2.0 to about 20.0 mg, per kg body weight of the animal or doses of about 0.01 to about 20.0 mg, preferably about 0.1 to about 5.0 mg, per kg body weight of the animal per day, for sustained medication, are generally suitable by oral or parenteral administration. By use of sustained release formulations or devices, the daily doses required over a period of months may be combined and administered to animals on a single occasion.
The compounds of the invention may be administered most advantageously with another parasiticidally effective material, such as an endoparasiticide, and/or an ectoparasiticide, and/or an endectoparasiticide. For example, such compounds include macrocyclic lactones such as avermectins or milbemycins e.g., ivermectin; pyratel (generally adminsitered as pyrantel pamoate) or an insect growth regulator such as lufenuron or methoprene.
By the term xe2x80x9cparasitesxe2x80x9d as used in the specification and claims is meant endoparasites and ectoparasites of warm-blooded animals, particularly ectoparasites. Preferably, fleas and/or ticks are controlled by the method of the present invention.
Illustrative of specific parasites of various host animals which may be controlled by the methods of this invention include arthropods such as:
Mites: Mesostigmata spp. e.g. mesostigmatids such as the chicken mite,
Dermanyssus gallinae; itch or scab mites such as Sarcoptidae spp. for example
Sarcoptes scabiei; mange mites such as Psoroptidae spp. including Chorioptes bovis and Psoroptes ovis; chiggers e.g. Trombiculidae spp. for example the north american chigger, Trombicula alfreddugesi;
Ticks: e.g., soft-bodied ticks including Argasidae spp. for example Argas spp. and Ornithodoros spp; hard-bodied ticks including lxodidae spp., for example Rhipicephalus sanguineus, and Boophilus spp.;
Lice: sucking lice, e.g., Menopon spp. and Bovicola spp.; biting lice, e.g., Haematopinus spp., Linognathus spp. and Solenopotes spp.;
Fleas: e.g., Ctenocephalides spp., such as dog flea (Ctenocephalides canis) and cat flea (Ctenocephalides felis); Xenopsylla spp. such as oriental rat flea [Xenopsylla cheopis]; and Pulex spp. such as human flea [Pulex irritans];
True bugs: e.g., Cimicidae or including the common bed bug (Cimex lectularius); Triatominae spp. including triatomid bugs also known as kissing bugs; for example Rhodnius prolixus and Triatoma spp.;
bloodsucking adult flies: (e.g., horn fly [Haematobia irritans], horse fly [Tabanus spp.], stable fly [Stomoxys calcitrans], black fly [Simulium spp.], deer fly [Chrysops spp.], louse fly [Melophagus ovinus], tsetse fly [Glossina spp.], mosquitoes [Culex spp., Anopheles spp., and Aedes spp.); and
parasitic fly maggots: (e.g., bot fly [Oestrus ovis and Cuterebra spp.], blow fly [Phaenicia spp.], screwworm [Cochliomyia hominivorax], cattle grub [Hypoderma spp.], fleeceworm.
The present invention also provides for the use of a compound of formula (I) or a salt thereof hereinbefore described as a therapeutic agent, preferably for animals, more preferably for domestic animals.
The veterinary composition may be sterile or non-sterile. It may be a liquid (e.g. aqueous) or solid (e.g., dry) composition, in particular a freeze-dried composition, which, by addition of water or another liquid, orally effective solutions may be prepared.
The present invention also provides for the use of a compound of formula (I) or a salt thereof as hereinbefore defined for the manufacture of a veterinary composition for the control of parasites in or on an animal.
In a further embodiment of the invention there is provided the use of a compound of formula (I) or salt thereof for controlling parasites in or on an animal without causing emesis of the animal.
Preferred is the use for orally administering the compound to the animal, which is preferably a domestic animal, highly preferred a cat or a dog.
In a further embodiment of the invention there is provided the use of a compound of formula (I) or salt thereof for the manufacture of a substantially non emetic composition, for controlling parasites in or on an animal, preferably for oral administering.
The present invention also relates to a method of cleaning animals in good health comprising the application to the animal of a compound of formula (I) or a salt thereof as hereinbefore defined to the animal.
The method of cleaning an animal is not a method of treatment by therapy of the animal body per se, because
(a) the animal is in good health and requires no substantial treatment to correct a deficiency of health;
(b) the cleaning of the animal is not intended to be done by veterinary personnel, but by persons interested in the cleaning of the animal; and
(c) the purpose of such cleaning is to avoid unpleasant conditions for humans and the environment in which humans inhabit so as to not infest the said humans with arthropods carried by the animal.
By xe2x80x9ccarrierxe2x80x9d is meant an organic or inorganic material, which can be natural or synthetic, and which is associated with the compound and which facilitates its application to the animal. This carrier is thus generally inert and should be arthropocidally acceptable. The carrier can be solid (e.g., clay, silicates, silica, resins, wax.) or liquid (e.g., water, alcohols, ketones, oil solvents, polar aprotic solvents) An example of an oil solvent is corn oil. An example of a polar aprotic solvent is dimethyl sulfoxide.
The compounds of the invention also have utility in the control of arthropod or nematode pests of plants. The active compound is generally applied to the locus in which arthropod or nematode infestation is to be controlled at a rate of about 0.005 kg to about 25 kg of active compound per hectare of locus treated, preferably 0.02 to 2 kg/ha. Under ideal conditions, depending on the pest to be controlled, the lower rate may offer adequate protection. On the other hand, adverse weather conditions, resistance of the pest and other factors may require that the active ingredient be used in higher proportions. For foliar application, a rate of 0.01 to 1 kg/ha may be used.
When the pest is soil-borne, the formulation containing the active compound is distributed evenly over the area to be treated in any convenient manner. Application may be made, if desired, to the field or crop-growing area generally or in close proximity to the seed or plant to be protected from attack. The active component can be washed into the soil by spraying with water over the area or can be left to the natural action of rainfall. During or after application, the formulation can, if desired, be distributed mechanically in the soil, for example by ploughing or disking.
Application can be prior to planting, at planting, after planting but before sprouting has taken place or after sprouting.
The compounds of the invention may be applied in solid or liquid compositions to the soil principally to control those nematodes dwelling therein but also to the foliage principally to control those nematodes attacking the aerial parts of the plants (e.g. aphelenchoides spp. and ditylenchus spp. listed above).
The compounds of the invention are of value in controlling pests which feed on parts of the plant remote from the point of application, e.g. leaf feeding insects are killed by the subject compounds applied to roots. In addition the compounds may reduce attacks on the plant by means of antifeeding or repellent effects.
The compounds of the invention are of particular value in the protection of field, forage, plantation, glasshouse, orchard and vineyard crops, or ornamentals and of plantation and forest trees, for example, cereals (such as maize, wheat, rice, sorghum), cotton, tobacco, vegetables and salads (such as beans, cole crops, curcurbits, lettuce, onions, tomatoes and peppers), field crops (such as potato, sugar beet, ground nuts, soyabean, oil seed rape), sugar cane, grassland and forage (such as maize, sorghum, lucerne), plantations (such as of tea, coffee, cocoa, banana, oil palm, coconut, rubber, spices), orchards and groves (such as of stone and pip fruit, citrus, kiwifruit, avocado, mango, olives, and walnuts), vineyards, ornamental plants, flowers and shrubs under glass and in gardens and parks, forest trees (both deciduous and evergreen) in forests, plantations and nurseries.
They are also valuable in the protection of timber (standing, felled, converted, stored or structural) from attack by sawflies (e.g. urocerus) or beetles (e.g. scolytids, platypodids, lyctids, bostrychids, cerambycids, anobiids), or termites, for example, reticulitermes spp., heterotermes spp., coptotermes.
They have applications in the protection of stored products such as grains, fruits, nuts, spices and tobacco, whether whole, milled or compounded into products, from moth, beetle and mite attack. Also protected are stored animal products such as skins, hair, wool and feathers in natural or converted form (e.g. as carpets or textiles) from moth and beetle attack; also stored meat and fish from beetle, mite and fly attack.
The disclosure in U.S. provisional application No. 60/168,658 from which this application claims priority is incorporated herein by reference.
This invention is further illustrated by the following examples, without limiting it thereto.